Overall hypothesis: Exposure of developing animals to severe stress causes an increase in the vulnerability of the brains of those animals to neuronal death, which persists into adulthood, leading to an increase in the susceptibility to neurological and psychiatric disease. Possible routes of rehabilitation include environmental enrichment, exercise, and specialized diets. We are seeking funds to further develop the tools necessary for collaborative studies on the impact of developmental stress and the vulnerability of the adult brain to neurotoxin exposure. Over the next two years, we have three major Specific Aims: Aim 1: To develop models of developmental stress in laboratory rats. Three models will be explored: (a) maternal deprivation, (b) nutritional deprivation, and (c) an inflammatory challenge. Aim 2: To obtain pilot data to see if developmental stress increases the vulnerability of the brain to neurotoxins. We will determine whether developmental stress increases the damage done by application of such neurotoxins as quisqualic acid and 6-hydroxydopamine. Special attention will be given to dopamine neurons in the brain, although other types of neurons also will be examined. Both behavioral and neurobiological indices of damage will be monitored. Aim 3: To further develop the research capacity of the University of Cape Town and the University of Stellenbosch through (a) attendance by faculty and trainees at international meetings, (b) attendance of key individuals at specific courses on research methodology, and (c) provision of instruction to faculty and trainees other professional skills such as oral and written communication, applying for research funds, and responsible conduct of research. Having accomplished these aims in 2003-2005 (FY 04 and FY05), we will submit a full proposal for research to begin in July 2005 (FY 06) that utilizes these tools to explore the molecular and cellular basis of DA neuron cell death and protection. Moreover, the methods and reagents that we develop will be made available to others in the field.